Breast cancer is the most common female malignancy in most industrialized countries, as it is estimated to affect about 10% of the female population during their lifespan. Although its mortality has not increased along with its incidence, due to earlier diagnosis and improved treatment, it is still one of the predominant causes of death in middle-aged women.
The primary treatment for breast cancer is surgery, either alone or combined with systemic adjuvant therapy (hormonal or cytotoxic) and/or post-operative irradiation. Most patients are cured with these treatments, but approximately 25-30% of women with node-negative disease and at least 50-60% of women with positive nodes, who appear to be disease-free after locoregional treatment, will relapse and need treatment for their metastatic disease. Thus, metastatic breast cancer is a significant and growing problem in oncology.
Approximately 30 to 40% of women with operable breast cancer eventually develop distant metastases. Metastatic breast cancer is commonly treated with anthracyclins, such as doxorubicin and epirubicin, which act via inhibiting the topoisomerase II (topoII) enzyme in cancer cells. A favorable response to topoII inhibitor-based chemotherapy improves post-chemotherapy survival and has a positive effect on the quality of life.
The response of patients to topoisomerase II inhibitors is widely variable. In addition, only 5 to 10% of breast cancer patients with overtly metastatic disease achieve complete clinical remission. In 30 to 50% of such cases, the response is partial, and the duration of response typically ranges from 6 to 24 months. In the remaining patients, either no objective response is detected, or the disease progresses despite ongoing treatment. The variation in the response rates highlights the need to identify patients who are likely to respond, and those who will obtain little or no benefit from a particular type of therapy or therapeutic regimen. Patients who are unlikely to respond to topoisomerase II inhibitors could be treated with alternative chemotherapeutic agents, such as taxanes, vinorelbine, or trastuzumab (HERCEPTIN). Unfortunately, the predictability of response is hindered by a lack of reliable markers. Indeed, conventional prognostic markers, such as the primary tumor size, axillary node status, and the histological grade of the tumor have not proven to be useful in the prediction of response to chemotherapy (Allred et al., Mod. Pathol., 11:155-168 [1998]). Also, controversial results have been reported for the use of S-phase fraction size, estrogen receptor characteristics, progesterone receptor characteristics or p53 expression, as predictors of patient response to chemotherapy. As such, there is a need for reliable markers for detecting patients with, or susceptible to, metastatic breast cancer. Indeed, reliable markers are urgently needed in order to facilitate the implementation of appropriate therapeutic regimens for these patients.